Continuous processes for the hydrolysis of cyanopyridines under substantially adiabatic conditions

ABSTRACT

Described are preferred processes for hydrolyzing substituted and unsubstituted cyanopyridines in the presence of a base and under substantially adiabatic conditions to produce pyridine substituted amides and/or pyridine substituted carboxylic acids. Preferred processes can be conducted in a variety of continuous reactors including cascades of reaction vessels, loop reactors or flow tube reactors. More preferred are the efficient and advantageous preparations of nicotinamide and niacin, which serve as important members of the B-vitamin complex.

BACKGROUND

This application claims priority of provisional application No.60/011,424 filed on Feb. 9, 1996.

This invention relates to a continuous process for the hydrolysis ofcyanopyridines, and in particular to such a process conducted undersubstantially adiabatic conditions. The hydrolysis conditions can becontrolled to produce amides, carboxylic acids or their mixtures asmajor products.

Several products resulting from the hydrolyses of cyanopyridines arewell-known products of commerce. For example, pyridine substitutedamides and carboxylic acids are important vitamins, precursors tomedicines and chemical intermediates. In the area of amides, the bestknown example includes niacinamide (also known as nicotinamide and3-pyridine carboxamide) and in the area of carboxylic acids, the bestknow example includes niacin (also known as nicotinic acid and3-pyridine carboxylic acid). Niacinamide and niacin, both commonlyreferred to as vitamin B₃, are members of the B-vitamin complex andprecursors of coenzymes I and II, and are important supplements to thediet of humans and animals. Pellegra related deaths in the United Statescaused by vitamin B₃ deficiency dropped from 7,358 in 1929, to 70 in1956, primarily as a result of increased availability of vitamin B₃.Higher growth rates occur in animals having diets supplemented withvitamin B₃ and in the case of ruminants, higher milk production alsooccurs. In 1985, the U.S. market for niacinamide and niacin wasestimated at 6,700 metric tons. See Kirk-Othmer, Encyclopedia ofChemical Technology, Third Edition, Vol. 24, pages 59-93 for a generaldiscussion of the B₃ Vitamins. Isonicotinic acid, a precursor toisonicotinic acid hydrazide (isoniazid) and related drugs used in thetreatment of tuberculosis can be prepared by the hydrolysis of4-cyanopyridine.

As to preparative methods for these compounds, cyanopyridines havefrequently been hydrolyzed in batch and continuous processes withcatalytic to stoichiometric excesses of a base. A majority of themethods reported have been batch processes. For example, 4-cyanopyridinein the presence of sodium hydroxide at a molar ratio of 1:(0.03-0.075)and at 120°-170° C. is reported to give isonicotinamide. See U.S.S.R. SU1,553,531 (1990); CA:113:78174f (1990). Similarly, 2-cyanopyridine isreported to react with sodium hydroxide at a molar ratio of1:(0.03-0.20) and at temperatures ranging from 100°-130° C. to give2-picolinamide. See U.S.S.R. SU 1,553,530 (1990); CA:113:78173e (1990).With a molar ratio of 4-cyanopyridine:sodium hydroxide of 1:(1.5-1.75)and a hydrolysis temperature of 50°-80° C., the reported hydrolysisproduct was isonicotinic acid. See U.S.S.R. SU 1,288,183; CA:106:176187n(1987). The hydrolysis of 3-cyanopyridine with excess ammonia at107°-109° C. for 12 hours was reported to give mixtures of nicotinamideand niacin. See J. Am Chem. Soc. 65, at pages 2256-7 (1943). In stillanother variation, the hydrolysis of 3-cyanopyridine has been reportedwith a polymeric base, Dowex 1X4 (in the hydroxide form), to yieldnicotinamide. See Dutch Patent Application No. 7706612-A; CA:90:186814e.U.S. Pat. No. 4,314,064 describes the continuous hydrolysis of3-cyanopyridine with 0.3 to 3.0 moles of an alkali metal hydroxide foreach 100 moles of cyanopyridine at pressures of between 3 to 20 bars andwith heating or cooling to maintain the prescribed reaction temperature.Similarly, 3-cyanopyridine is reported to react in a continuous processwith aqueous ammonia at a molar ratio of 1:0.5 and a contact time of40-50 minutes at 200°-260° C. to give nicotinamide. See Journal ofApplied Chemistry of the USSR (English Translation: 45:2716-2718 (1972).

As an alternative to the hydration of cyanopyridines in the presence ofbases, bacterial and enzymatic hydrolysis processes have been studied.U.S. Pat. No. 5,395,758, assigned to Sumitomo Chemical Company Ltd.,describes the conversion of 2-, 3-, and 4-cyanopyridine into theircorresponding amides using cultured broths of an Agrobacterium bacteria.Japanese Patent No. 9300770000, assigned to Nitto Chemical Ind. Co.Ltd., describes the hydration of aromatic nitrites, including 3- and4-cyanopyridine, using the action of Corynebacterium or Nocardiabacterium to give the corresponding aromatic amides with highselectivities.

In view of this background there remains a need and demand for acontinuous process for the hydrolysis of cyanopyridines which providesfor increased production rates while also providing high yields andproduct selectivity. Additionally, the continuous process should becapable of being operated employing starting materials which are readilyavailable, and in simple equipment requiring minimal controls. Thepresent invention addresses these needs.

SUMMARY

A feature of the present invention is the discovery that the continuoushydrolysis of cyanopyridines can be carried out in the presence of abase and under substantially adiabatic conditions to provide a vigorousreaction which surprisingly leads to increased production rates withhigh yields and selectivities. Thus one preferred embodiment of theinvention provides a continuous process for hydrolyzing a cyanopyridine(for example 2-, 3-, or 4-cyanopyridine) by combining two or more feedstreams to form a reaction mixture containing the cyanopyridine, water,and a base (for example, ammonia, an alkali metal hydroxide or an alkalimetal carbonate) and reacting the reaction mixture under substantiallyadiabatic conditions. Processes of the invention can be carried out in avariety of continuous systems including for example a simple flow tube,require no temperature control other than an initiation temperature andcan be substantially completed in less than a minute. For a givencyanopyridine, the required initiation temperature is a function of thecyanopyridine's reactivity toward hydrolysis and its concentration inaddition to the base utilized and the ratio of that base to thecyanopyridine. The ratio of base to cyanopyridine also affects whetherthe major product is an amide or a carboxylic acid. Preferred hydrolysesof 2-cyanopyridine, 3-cyanopyridine and 4-cyanopyridine can becontrolled to produce picolinamide, picolinic acid, nicotinamide,niacin, isonicotinamide or isonicotinic acid at surprisingly highproduction rates, with unexpected selectivities and surprisingly shortreaction times.

Another preferred embodiment of the present invention provides a processwhich includes the steps of combining a first stream containing acyanopyridine with a second stream containing water and a base, where atleast one of the streams is heated to a temperature of about 20° toabout 300° C., and passing the streams after they are combined through areaction zone, to cause the hydrolysis to proceed under substantiallyadiabatic conditions. The first stream can include only a cyanopyridineas a melt or can additionally include water and/or anothernon-interfering solvent. Although several reactor designs including aseries of cascade reactors, loop reactors, or flow tubes can provide asuitable reaction zone a flow tube reactor is preferred. Preferredhydrolysis reactions include the hydrolysis of 3-cyanopyridine withalkali metal hydroxides such as sodium or potassium hydroxide to givenicotinamide or niacin in high yields and conversions with a minimum ofimpurities.

DESCRIPTION

For the purposes of promoting an understanding of the principles of theinvention, reference will now be made to certain of its embodiments andspecific language will be used to describe the same. It willnevertheless be understood that no limitation of the scope of theinvention is thereby intended, such alterations, further modificationsand applications of the principles of the invention as described hereinbeing contemplated as would normally occur to one skilled in the art towhich the invention relates.

As indicated above, the present invention provides unique processes forthe continuous hydrolyses of cyanopyridines in the presence of a baseunder substantially adiabatic conditions, which surprisingly lead toincreased production rates with high yields and selectivities. In thisregard, the term "substantially adiabatic conditions" is meant toinclude conditions wherein substantially all of the heat generated bythe hydrolysis reaction is retained within the reaction mixture duringthe period of reacting. That is, substantially no effort is made to coolthe combined reactants within the reaction zone during the period ofreacting. As a result, heat from the hydrolysis reaction is usuallygenerated faster than it can be dissipated to surrounding regions andthe temperature of the reaction mixture within the reaction zone reachessubstantially that temperature caused by the uncontrolled exotherm ofthe hydrolysis reaction. Typically, the temperature of the reactionmixture increases by at least about 20° C. "Reaction zone" is meant toinclude a region within a continuous reactor where a cyanopyridinecombined with a base undergoes a rapid exothermic reaction producing thehydrolysis product. Applicant's preferred process can be carried out ina variety of continuous systems, only requires control of the flow ratesand initiation temperature and is completed within less than aboutthirty seconds after initiation has occurred.

The continuous hydrolysis of cyanopyridines according to embodiments ofthe preferred process produces primarily amides, carboxylic acids ortheir mixtures. 2,- 3-, and 4-Cyanopyridines are hydrolyzed with theapplicants' preferred process to give picolinamide, picolinic acid,nicotinamide, niacin, isonicotinamide and isonicotinic acid. Inaddition, a wide variety of substituted and unsubstituted cyanopyridinesare also suitable for use in the invention. Representative substituentsinclude groups such as alkyl having up to about 9 carbon atoms, aryl,cyano, amino, alkylamino, hydroxy, and halo (e.g. --Cl and --Br) etc.Suitable substituents may remain unchanged as a result of the hydrolysisreaction or may be transformed during hydrolysis into a new substituent.The preferred cyanopyridines for use in the hydrolysis process includenon-substituted cyanopyridines (2-cyanopyridine, 3-cyanopyridine, and4-cyanopyridine) and substituted cyanopyridines with up to fouradditional groups which do not detrimentally interfere with thehydrolysis reaction and are either commercially available or can beobtained by methods known to the art and literature. More preferredcyanopyridines are non-substituted 2-cyanopyridine, 3-cyanopyridine, and4-cyanopyridine, for example as can be obtained from Reilly Industries,Inc., of Indianapolis, Ind. and the Cambrex Corporation, EastRutherford, N.J. Although not necessary for the present invention, it ispreferred that the cyanopyridines used be of high purity, for exampleabout 95 to about 99.9% or more pure.

A variety of bases are known to facilitate hydrolysis reactions and theparticular base employed is not critical to the broad aspects of theinvention. Suitable bases for use in the invention generally includethose bases compatible with the aqueous hydrolysis system whichaccelerate the hydrolysis of cyanopyridines. Preferred bases for use inthe invention are ammonia, alkali metal hydroxides such as sodium orpotassium hydroxide and alkali metal carbonates such as sodium orpotassium carbonate. Although not required, the bases are commonly usedin solution, more preferably in water. Preferred aqueous solutions ofbase have contained from about 5 to about 50% by weight base.

Processes of the invention can be conducted with varying amounts ofwater relative to cyanopyridine so as to control the reaction product,to improve the products flow through the reactor, and to effect themagnitude of the temperature increase caused by the uncontrolledexothermic hydrolysis reaction. The preferred amount of water forcontrol of reaction product depends on the number of cyano groups on thecyanopyridine undergoing hydrolysis and whether amide or carboxylic acidgroups are desired. For hydration, each cyano group reacts with one (1)molecule of water to give an amide group and two (2) molecules of waterto give a carboxylic acid group. As a result, the preferred number ofmoles of water per mole of cyanopyridine utilized for product controlcan be determined for each cyanopyridine by adding (a) the number ofcyano groups being hydrolyzed to amide groups multiplied by one (1), and(b) the number of cyano groups being hydrolyzed to carboxylic acidgroups multiplied by two (2). For preferred processes, at least a slightexcess of water is typically used. It can be added separately, with thecyanopyridine, with the base or some combination thereof. Typically,water is added with both the cyanopyridine and the base for feed toprocesses of the invention. Preferred cyanopyridine solutions have beenfrom about 20% to about 85% by weight cyanopyridine in water, with morepreferred cyanopyridine solutions containing from about 35% to about 70%by weight cyanopyridine, for amide and for carboxylic acid formation.

In preferred processes, a cyanopyridine, at least one base, andsufficient water are combined in a continuous manner to give a reactionmixture at an initial temperature sufficient to initiate and maintainhydrolysis without additional heating and sufficient to cause the rapidhydrolysis of the cyanopyridine. This initial temperature is referred toherein as the initiation temperature. To initiate hydrolysis whenheating is necessary, at least one reactant stream can be preheated to atemperature sufficient to cause the reaction mixture to reach theinitiation temperature and begin hydrolysis immediately upon combiningthe reactant streams. The amount of heating necessary is a function ofthe quantities and heat capacities of the various streams being combinedas well as the concentrations of the reactants. For aqueouscyanopyridine solutions ranging between about 20% to about 85% by weightcyanopyridine, initiation temperatures between about 20° to about 300°C. have proven sufficient. For amide formation, initiation temperaturesof about 60° to about 140° C. have been most preferred while forcarboxylic acid formation, initiation temperatures of about 60° to about200° C. have been most preferred. In advantageous processes, thehydrolysis is rapid and exothermic, causing a rapid increase in thetemperature of the combined reactant streams within the reaction zone.For example, in more advantageous processes, the hydrolysis reaction hascaused the temperature of the reaction mixture to increase by at leastabout 20° C. and the reaction is completed within less than about 30seconds and typically in less than about 5 seconds.

The choice of base and its amount relative to the cyanopyridine can becontrolled to cause the product to contain primarily a preferred amideor a preferred carboxylic acid. With stronger bases such as sodium andpotassium hydroxide smaller quantities of base are adequate, while withweaker bases such as ammonia, larger quantities of base are required.Control of these parameters to achieve the desired products or productmixtures will be well within the purview of one skilled in the art giventhe teachings herein. Because bases can be either monobasic or dibasicand cyanopyridines can have more than one cyano group, the relativeamounts of these reactants can be effectively understood in terms ofequivalents. The number of equivalents of base can be determined bymultiplying the number of moles of a base (determined in the usualmanner) by the number of protons a mole of that base will react with.The number of equivalents of cyanopyridine can be determined bymultiplying the number of moles of a cyanopyridine (determined in theusual manner) by the number of cyano groups present. The ratio of baseto cyanopyridine will be a ratio of the number of equivalents of baseper equivalents of cyanopyridine. In the preferred process, the ratio ofbase to cyanopyridine can vary depending on the hydrolysis productdesired, the strength of the base utilized and the amount of waterpresent. Generally, amide formation is favored when the ratio ofequivalents of base to equivalents of cyanopyridine is about (0.01 to50):100 and acid formation is favored when the ratio of equivalents ofbase to equivalents of cyanopyridine is about (50 to 200):100.

Although the present continuous hydrolysis can be carried out in avariety of customary continuous processing apparatuses such as cascadesof reaction vessels, loop reactors or flow tubes, a flow tube reactor ispreferred. For the preferred process, at least two reactant streamstogether containing cyanopyridine, water, and base are fed into areactor, with sufficient heat applied to at least one of the reactantstreams to cause the combined streams to reach an initiationtemperature. Although not required, the reactant streams can passthrough a mixing region immediately prior to entering the reactor or asan initial stage of the reactor. The mixing region can include a staticmixer, a region containing packing materials or other mechanical formsknown in the art. The reactor can also be equipped to operate at ambientpressure or at a prescribed pressure above atmospheric pressure. Becauseof the uncontrolled exothermic nature of the hydrolysis, reactorsdesigned to operate above atmospheric pressure have generally beenequipped with a pressure relieve valve vented to a catch pot and setbelow the pressure limit of the reactor. After hydrolysis, the reactionproducts exit the reactor and can pass into a receiver for futureprocessing or can pass directly into a recovery system.

For the preferred continuous processes high production rates,selectivities, and yields are typically obtained. For instance, fornicotinamide formation by hydrolysis of 3-cyanopyridine, productionrates ranging from between about 200 to several thousand kg per hour perliter of reactor volume can be obtained, with the applicant's work insystems to date readily achieving about 200 to about 1000 kg per hourper liter and more often about 400 to about 900 kg per hour per liter.Similar production rates can be and have been obtained for thehydrolysis of 3-cyanopyridine to niacin. The yields of amides andcarboxylic acids utilizing the preferred continuous process havetypically ranged between about 95% to about 99.5% with usually betweenabout 0 to about 0.2% of unreacted nitrile remaining. By-products,either amide or carboxylic acid, have typically ranged between about 1to about 5%.

Products from the continuous hydrolysis can be isolated by conventionalmethods. These methods include known batch or continuous crystallizationmethods, batch or continuous evaporative procedures, or combinationsthereof. Niacinamide suitable for feed grade applications can beobtained by continuously dehydrating or drying the hydrolysis mixtureutilizing a falling film evaporator and cooling belt technology, forexample as described in U.S. Pat. No. 4,314,064. Carboxylic acidproducts can be recovered by first reacting the basic salt with an acidand isolating the free carboxylic acid by conventional methods such ascrystallization. The hydrolysis products obtained by the process of thepresent invention are useful as vitamins (i.e. niacinamide and niacin),as chemical intermediates in the manufacture, for example, of productsused in the agricultural and pharmaceutical industries.

For the purposes of promoting a further understanding of the presentinvention and its preferred features and embodiments, the followingexamples are being provided. It will be understood, however, that theseexamples are illustrative, and not limiting, in nature.

Examples 1-10 were carried out in a 1 liter autoclave to simulate thefirst stage of a cascade of reaction vessels. Examples 11-14 werecarried out in a flow tube reactor. Hydrolysis reactions to givepyridine substituted carboxylic acids have given similar results in bothreactors. However, better selectivity for amide formation has beenobtained in the flow tube reactor. For all examples the compositions ofsolutions are given in weight percents.

EXAMPLES 1-10

Examples 1-10 set forth in Table 1 were conducted using the followingprocedure. An aqueous solution of the indicated cyanopyridine(abbreviated "CN") was heated in a stirred stainless steel autoclaveequipped with a heating mantle to an initiation temperature, heating wasdiscontinued and an aqueous solution of the indicated base was quicklyinjected (typically in less than 5 seconds). When the temperature of thereaction mixture began to drop, the maximum temperature was noted, theheating mantle dropped and the autoclave was cooled rapidly in coldwater. The reaction mixture was analyzed by HPLC to determine theamounts of the corresponding amide, carboxylic acid and cyanopyridine.As examples 1-10 demonstrate, the cyanopyridine concentrations, choiceof base, amount of base, and the initiation temperature can becontrolled in the hydrolysis of cyanopyridines under substantiallyadiabatic conditions to produce pyridine substituted amides andcarboxylic acids. The choice of conditions produces high yields of thepyridine substituted amide or carboxylic acid.

                                      TABLE 1                                     __________________________________________________________________________    Example No.                                                                            1    2    3    4   5   6    7    8    9    10                        __________________________________________________________________________    Cyanopyridine                                                                          3-CN 3-CN 3-CN 3-CN                                                                              3-CN                                                                              4-CN 4-CN 2-CN 3-CN 2-CN                      concentration                                                                          42.3%                                                                              65.2%                                                                              77.3%                                                                              22.1%                                                                             63.3%                                                                             51.8%                                                                              63.7%                                                                              51.8%                                                                              51.8%                                                                              51.8                      amount, mL                                                                             182  177  174  177 152 186  151  186  186  186                       Base     NaOH NaOH NaOH NaOH                                                                              NaOH                                                                              NH.sub.3                                                                           NH.sub.3                                                                           NH.sub.3                                                                           NH.sub.3                                                                           Na.sub.2 CO.sub.3         concentration                                                                          10%  10%  10%  40% 40% 29%  29%  29%  29%  15%                       amount, mL                                                                             12   18   21   28  70  10   60   10   10   11                        Initial Temperature                                                                    125° C.                                                                     115° C.                                                                     105° C.                                                                     200° C.                                                                    200° C.                                                                    115° C.                                                                     200° C.                                                                     115° C.                                                                     115° C.                                                                     115° C.            Maximum  147° C.                                                                     152° C.                                                                     155° C.                                                                     205° C.                                                                    216° C.                                                                    116° C.                                                                     200° C.                                                                     117° C.                                                                     115° C.                                                                     128° C.            Temperature                                                                   Ratio of 14.3:100                                                                           14.3:100                                                                           14.3:100                                                                           104:100                                                                           104:100                                                                           15.9:100                                                                           95.2:100                                                                           15.9:100                                                                           15.9:100                                                                           0.9:100                   Base:Cyanopyridine                                                            Products                                                                      amide    94.2%                                                                              94.8%                                                                              95.1%                                                                              1.7%                                                                              8.0%                                                                              25.4%                                                                              45.1%                                                                              0.5% 2.9% 73.1%                     cyanopyridine                                                                          0.2% 0.0% 0.2% 0.0%                                                                              0.0%                                                                              73.2%                                                                              51.8%                                                                              99.4%                                                                              97.1%                                                                              26.1%                     carboxylic acid                                                                        5.6% 5.2% 4.7% 98.3%                                                                             92.0%                                                                             1.3% 3.1% 0.1% 0.0% 0.8%                      __________________________________________________________________________

EXAMPLES 11-14

The continuous hydrolysis of 3-cyanopyridine was carried out in aninsulated flow tube reactor having a length of 5.5 feet and an innerdiameter of 1.049 inches and no means for cooling. At one end, thereactor was connected in series to a static mixer, a heater, and a pumpfor introducing the 3-cyanopyridine solution. Between the static mixerand the pump, was an inlet pipe for introducing an aqueous solution ofsodium hydroxide. Thermocouples were placed: (a) between the heater andthe static mixer, (b) at the entry of the reactor and (c) near the exitof the reactor. At its exit, the reactor was connected to a receiverequipped with a water condenser. Between the reactor and the receiverwere placed (a) nearer the reactor, a pressure relief valve and (b)nearer the receiver a back pressure regulator set at approximately 200psi or alternatively, a ball valve restricted to create the desiredpressure.

For Example 11, an aqueous solution containing 60% by weight of3-cyanopyridine was fed through the heater at a uniform rate of 142gallons/hour, increasing its temperature to 115° C. A 7% aqueoussolution of sodium hydroxide was metered into the 3-cyanopyridine streamat a uniform rate of 5 gallons/hour and the combined streams fed intothe reactor through the static mixer. The combined reactants entered theflow tube reactor at a temperature of 116° C., reached a temperature of156.9° C. within about 4 seconds and immediately exited the reactor andpassed into the holding vessel. The ratio of sodium hydroxide tocyanopyridine was 1.1:100. A sample of the hydrolysis product wasanalyzed and found to contain on a water free basis: a) 96.04%nicotinamide; b) 0.23% 3-cyanopyridine; and c) 3.73% sodium nicotinate.Table 2 summarizes the results from Examples 11-14 carried out in a flowtube reactor utilizing the method described above. Other substitutedcyanopyridines, including 2-cyanopyridine and 4-cyanopyridine, can behydrolyzed in the flow tube reactors to give amides, carboxylic acids,or mixtures. For the hydrolysis of 2-cyanopyridine or its derivatives togive the carboxylic acid, maximum temperatures above about 135° C.should be avoided to prevent decarboxylation of the initially formedcarboxylic acid.

                  TABLE 2                                                         ______________________________________                                        Example No.     11      12      13    14                                      ______________________________________                                        3-Cyanopyridine                                                               concentration   60%     60%     60%   60%                                     flow-rate, gal/hr                                                                             142     161     140   145.6                                   Sodium Hydroxide                                                              concentration   7%      6.6%    6.6%  8.1%                                    flow-rate, gal/hr                                                                             5       2.2     10.8  6.64                                    Initiation Temperature, °C.                                                            115     120     115   110                                     Maximum Temperature, °C.                                                               156.9   190     195.8 >200                                    NaOH:Cyanopyridine                                                                            1.1:100 0.4:100 2.3:100                                                                             1.7:100                                 Product                                                                       nicotinamide, % 96.04   93.17   96.04 96.99                                   cyanopyridine, &                                                                              0.23    5.66    0.00  0.00                                    sodium nicotinate, %                                                                          3.73    1.16    3.96  3.01                                    ______________________________________                                    

While the invention has been illustrated and described in detail in theforegoing description, the same is to be considered as illustrative andnot restrictive in character, it being understood that only thepreferred embodiment has been shown and described and that all changesand modifications that come within the spirit of the invention aredesired to be protected.

All publications cited herein are indicative of the level of skill inthe art and are hereby incorporated by reference as if each had beenindividually incorporated by reference and fully set forth.

What is claimed is:
 1. A continuous process for the hydrolysis of acyanopyridine, comprising continuously combining two or more feedstreams to provide a reaction mixture including a cyanopyridine, water,and a base, and reacting the reaction mixture under substantiallyadiabatic conditions.
 2. The process of claim 1, wherein thecyanopyridine is selected from the group consisting of 2-cyanopyridine,3-cyanopyridine, and 4-cyanopyridine.
 3. The process of claim 2, whereinsaid reacting is initiated at a temperature of at least about 20° C.,and wherein said base is present in an amount less than 50 equivalentsof base per 100 equivalents of cyanopyridine.
 4. The process of claim 3,which includes reacting about 0.01 to about 10 equivalents of base per100 equivalents of the cyanopyridine and said reacting is initiated at atemperature of about 60° to about 140° C. to and forms a productcomprising a pyridine substituted amide.
 5. The process of claim 4,wherein said base is ammonia.
 6. The process of claim 5, wherein saidcyanopyridine is 3-cyanopyridine and said pyridine substituted amide isniacinamide.
 7. The process of claim 4, wherein said base is an alkalimetal hydroxide.
 8. The process of claim 7, wherein the cyanopyridine is3-cyanopyridine, the alkali metal hydroxide is sodium or potassiumhydroxide and the product comprises niacinamide.
 9. The process of claim4, wherein the base is an alkali metal carbonate.
 10. The process ofclaim 9, wherein the cyanopyridine is 3-cyanopyridine, the alkali metalcarbonate is sodium or potassium carbonate and the product comprisesniacinamide.
 11. The process of claim 10, wherein said process includesrecovering niacinamide.
 12. The process of claim 1, wherein thecyanopyridine is selected from the group consisting of 2-cyanopyridine,3-cyanopyridine, and 4-cyanopyridine.
 13. The process of claim 12,wherein said reacting is initiated at a temperature of at least about20° C., and wherein said base is present in an amount of at least 50equivalents of base per 100 equivalents of cyanopyridine.
 14. Theprocess of claim 13, which includes reacting about 50 to about 200equivalents of base per 100 equivalents of the cyanopyridine, andwherein said reacting is initiated at a temperature of about 60° toabout 200° C. and forms a product comprising a pyridine substitutedcarboxylic acid.
 15. The process of claim 14, wherein the base isammonia.
 16. The process of claim 15, wherein the cyanopyridine is3-cyanopyridine and the product comprises niacin.
 17. The process ofclaim 14, wherein the base is an alkali metal hydroxide.
 18. The processof claim 17, wherein the cyanopyridine is 3-cyanopyridine, the alkalimetal hydroxide is sodium or potassium hydroxide and the productcomprises niacin.
 19. The process of claim 14, wherein the base is analkali metal carbonate.
 20. The process of claim 19, wherein thecyanopyridine is 3-cyanopyridine, the alkali metal carbonate is sodiumor potassium carbonate and the product comprises niacin.
 21. Acontinuous process for the hydrolysis of a cyanopyridine, comprising thesteps of:combining a first stream containing said cyanopyridine with asecond stream containing water and a base, wherein at least one of thestreams is heated to a temperature of about 20° to about 300° C.; andpassing the streams after said combining through a reaction zone andcausing a hydrolysis reaction to proceed under substantially adiabaticconditions.
 22. The process in claim 21, wherein the first streamcontains about 20 to about 85% by weight cyanopyridine and the secondstream contains about 5 to about 50% by weight of said base.
 23. Theprocess in claim 22, which includes reacting about 0.01 to about 10equivalents of base per 100 equivalents cyanopyridine, said reactingbeing initiated at a temperature of about 60° to about 140° C. andforming a product comprising a substituted amide.
 24. The process inclaim 23, wherein the cyanopyridine is 3-cyanopyridine, the base issodium or potassium hydroxide and the product comprises niacinamide. 25.The process of claim 22, which includes reacting at least 50 equivalentsof base per 100 equivalents of cyanopyridine, said reacting beinginitiated at a temperature of about 60° to about 200° C. and forming aproduct comprising a substituted carboxylic acid.
 26. The process ofclaim 25, wherein the cyanopyridine is 3-cyanopyridine, the base issodium or potassium hydroxide and the product comprises niacin.
 27. Theprocess of claim 21, wherein said first stream contains 3-cyanopyridineand said hydrolysis reaction is conducted in a flow tube reactor. 28.The process of claim 27, wherein said first stream contains from about20% to about 85% by weight 3-cyanopyridine.
 29. The process of claim 28,wherein the base is selected from a group consisting of ammonia, sodiumhydroxide, sodium carbonate, potassium hydroxide, and potassiumcarbonate.
 30. The process of claim 29, wherein the hydrolysis reactionis initiated at a temperature of about 20° to about 300° C. and the baseis sodium or potassium hydroxide.
 31. The process of claim 30, whereinsaid base is present in an amount less than about 50 equivalents of baseper 100 equivalents of 3-cyanopyridine, the hydrolysis reaction isinitiated at a temperature of about 60° to about 140° C. and forms aproduct comprising niacinamide.
 32. The process of claim 30, wherein thebase is present in an amount of at least 50 equivalents of base per 100equivalents of 3-cyanopyridine, the hydrolysis reaction is initiated ata temperature of about 60° to about 200° C. and forms a productcomprising niacin.
 33. A continuous process for the hydrolysis of acyanopyridine, comprising continuously reacting a reaction mixtureincluding cyanopyridine, water and a base, wherein said reacting isinitiated at a temperature of at least 20° C. and produces an increasein the temperature of said reaction mixture of at least 20° C.
 34. Theprocess of claim 33, wherein the cyanopyridine is 3-cyanopyridine andsaid process includes reacting about 0.01 to about 10 equivalents ofbase per 100 equivalents of 3-cyanopyridine and forms a productcomprising niacinamide.
 35. The process of claim 34, wherein said baseis selected from the group consisting of ammonia, sodium hydroxide,sodium carbonate, potassium hydroxide and potassium carbonate.
 36. Theprocess of claim 35, wherein the cyanopyridine is 3-cyanopyridine andsaid process includes reacting at least 50 equivalents of base per 100equivalents of 3-cyanopyridine and the product comprises niacin.
 37. Theprocess of claim 36, wherein said base is selected from the groupconsisting of ammonia, sodium hydroxide, sodium carbonate, potassiumhydroxide and potassium carbonate.
 38. The process of claim 33, whereinsaid reacting is substantially complete in less than about 30 seconds,and in that 30 seconds produces an increase in the temperature of saidreaction mixture of at least about 20° C.
 39. The process of claim 33,wherein substantially all heat generated by said reacting is retainedwithin the reaction mixture during said reacting.
 40. A continuousprocess for the hydrolysis of a cyanopyridine, comprising the stepsof:continuously forming and passing through a reaction zone, a reactionmixture including the cyanopyridine, water and a base; initiating anexothermic hydrolysis reaction of the reaction mixture in the reactionzone; and retaining in said reaction mixture during said hydrolysisreaction, substantially all heat generated by said hydrolysis reaction.